The abuse of psychostimulants among adolescents is continuously rising, but little is known about the long-term consequences of this practice. One of the major concerns is that early drug exposure may cause long-lasting adaptations which render the organism more susceptible to drug abuse and relapse later in life. Research on animal models of drug abuse has traditionally centered on adult subjects, with a paucity of studies on adolescent animal models. Studies in adult animals have indicated that repeated exposure to cocaine and amphetamine derivatives causes long-term susceptibility to the psychomotor stimulating and rewarding effects of these drugs. In a series of studies we have demonstrated that the nitrergic system (neuronal nitric oxide synthase; nNOS) has a major role in dopamine-mediated effects of psychostimulants in adult mice. In preliminary studies we found that in contrary to adult mice deficient in the nNOS gene (nNOS KO mice) which are resistant to psychomotor sensitization, adolescent nNOS KO mice developed psychomotor sensitization following repeated administration of methamphetamine. However both adolescent and adult wild-type (WT) mice were equally sensitive to the drug. Our working hypothesis is that although adolescents and adults develop sensitization to psychostimulants, there is an ontogeny-dependent difference in the mechanism that underlies this process in each age cohort, and that the expression of the nNOS gene in adolescence is essential for the persistence of long-term susceptibility to psychostimulants in adulthood. The overall aim of this project is to investigate the role of nNOS in ontogeny- and gender-dependent variations in the responsiveness to psychomotor stimulation and drug-seeking behavior, and the extent to which structural adaptations of nNOS-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons in mesolimbic and corticostriatal circuits correlate with the behavioral phenomena. The effects of cocaine, MDMA (ecstasy) and methylphenidate (Ritalin) on a) locomotor activation, b) conditioned place preference and c) the immunohistochemistry of nNOS- and TH-positive neurons will be investigated in WT and nNOS KO mice. Results of these studies would provide new information on mechanisms that underlie the development of hypersensitivity to these drugs from adolescence through adulthood.